20.500.12556/RUL-150946 Sinteza in biološko vrednotenje kombinatorne knjižnice spojin pridobljenih z bakrom(I) katalizirano azid-alkin cikloadicijo Synthesis and biological evaluation of combinatorial compound library prepared with copper(I) catalysed azide-alkyne cycloaddition Knjižnice spojin so zbirke velikega števila spojin, ki se jih navadno uporablja pri rešetanju visoke zmogljivosti z namenom odkrivanja zadetkov v procesu identifikacije novih zdravilnih učinkovin. Farmacevtska podjetja so skozi leta svojega obstoja ustvarila obsežne zbirke različnih spojin, bodisi s sintezo novih in modifikacijo že obstoječih struktur, ali z izoliranjem različnih spojin iz naravnih produktov. Na trgu obstajajo tudi komercialno dostopne knjižnice spojin, ki jih je moč kupiti. Če pa želi posameznik ustvariti svojo knjižnico spojin s sintezo vsake spojine posebej, bi za to potreboval leta. Odgovor za to bi lahko bila klik kemija, ki se osredotoča na spojine, katere lahko sintetiziramo iz modularnih blokov, združevanje le teh pa mora biti preprosto kot zapetje dveh delov zaponke. Zato morajo biti reakcije enostavne, modularne, širokega obsega in morajo dajati stranske produkte, ki se jih lahko zlahka znebimo. Ena od teh reakcij je Huisgenova 1,3-dipolarna cikloadicija med azidom in alkinom, pri kateri nastane 1,4-triazolni izomer, pri čemer morajo biti prisotni Cu(I) ioni. V okviru magistrske naloge smo sintetizirali in očistili več spojin azidov in dialkinov, s katerimi smo kasneje izvedli klik reakcije z namenom priprave knjižnice spojin. V vsako klik reakcijo so vstopali različni azidi in eden od pripravljenih dialkinov. Pri tem sta z vsako molekulo dialkina reagirali dve različni ali enaki molekuli azida, kar nam je na koncu dalo n2 (n=število azidov v reakciji) različnih spojin. Tako smo pri vsaki klik reakciji dobili mešanico spojin ditriazolov, pri čemer je vsaka mešanica predstavljala knjižnico spojin. Potek klik reakcij in nastanek ditriazolov smo kasneje potrdili z analizo na masnem spektrometru. Vsaki zmesi smo določili tudi zaviralno aktivnost na encimu MurA in minimalno inhibitorno koncentracijo (MIC) na bakterijah E. coli in S. aureus. Nobena od treh pripravljenih knjižnic spojin ni izkazovala zaviralne aktivnosti na izbranem encimu in vrstah bakterij, kar pa ne pomeni, da katera od spojin v pripravljenih knjižnicah spojin ne zavira katerega drugega encima. Velikokrat namreč tudi rešetanja veliko večjih knjižnic ne dajo pozitivnega rezultata. Chemical compound libraries are big collections of many different chemical entities, which are normally used in high throughput screening with the intention of finding new hit molecules in the drug discovery process. Different pharmaceutical companies have through the years of their existence each created large compound libraries either by synthesis of new chemical compounds and modification of the already existing structure, or by isolation from different natural products. Commercially available compound libraries are also available, but to create one from scratch, it would take several years to be completed. The answer to that could be click chemistry, which focuses on compounds that can be created by joining together different modular blocks. The joining of this blocks must be as simple as joining together a buckle. This requires simple, modular, broad chemical reactions which create easily removable side products. One of few suitable candidates is Huisgen 1,3-dipolar cycloaddition between an azide and alkyne which gives us a 1,4-triazole isomer in the presence of Cu(I) ions. Within this master thesis we synthesized and purified several azide and dialkyne compounds which we later used to prepare different compound libraries with the help of click reactions. In each of the click reactions azides reacted with one of the prepared dialkyne compounds. Each dialkyne could react with two different or two identical azide compounds which gave us n2 (n=number of azides in click reaction) of different ditriazole compounds with each click reaction. Each click reaction represented a different compound library. Later we confirmed the formation of ditriazole compounds with mass spectrometer. We also tested inhibitory properties of each prepared library on the MurA enzyme and minimal inhibitory concentration (MIC) on E. coli and S. aureus bacteria. None of the three prepared chemical libraries showed any inhibitory activity against the selected enzyme or bacteria but that does not exclude the possibility that one of the compounds inhibits some other enzyme. odkrivanje novih zdravilnih učinkovin klik kemija knjižnica spojin azid-alkin cikloadicija afinitetna selekcijska masna spektrometrija drug discovery click chemistry chemical compound library azide-alkine cycloaddition affinity selection-mass spectrometry true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2023-09-26 08:45:25 2023-09-26 08:45:30 2023-09-27 03:59:25 0000-00-00 00:00:00 2023 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 101634 18261.pdf 18261.pdf 1 948F6483E52978E4338CCE6DC234E982 aa9161e513f8cc1b33bbe5f7be6386ccfebb1c742e78d1273e827c7f25a35e5b 48a8eac6-5c38-11ee-9c9a-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=175819 Fakulteta za farmacijo 0 0 0